One of the greatest challenges in modern neuroscience is to achieve an understanding of how the brain acquires, stores and retrieves information. A particularly exciting new development in exploring this general question is the recent identification of the possible role of growth factors, once considered to function mainly in brain development, in synaptic plasticity and memory in the adult. While this idea is truly seminal, a causal role of growth factors in memory formation has yet to be established. Thus the broad, long-term goal of this research project is to elucidate in mechanistic detail the ways in which growth factors participate in the formation and maintenance of long-term memories. To achieve this goal we will explore two interrelated Specific Aims. In AIM 1 we will test the hypothesis that growth factor signaling plays an essential role in memory formation and its underlying synaptic plasticity, and in Aim 2 we will test the hypothesis that growth factors re-employ molecular signaling cascades originally engaged in development in the service of adult memory formation and synaptic plasticity. Of direct relevance to the health-related mission of the NIMH, these two Aims will address a major challenge in mental health: to achieve a basic understanding of the brain mechanisms that are engaged in normal memory formation, and how those mechanisms are impaired when memory is compromised by disease or injury. Thus, understanding the molecular mechanisms whereby growth factors contribute to normal memory formation can provide an important and novel means of identifying therapeutic targets for a variety of health related cognitive disorders. To directly explore how growth factors participate i memory formation requires multiple levels of analysis (behavioral, cellular, synaptic, and molecular levels). Aplysia californica is a powerful model system to address this question because it allows such a simultaneous multi-level analysis, as well as a time-dependent analysis of when critical changes occur, and a spatial analysis of where changes occur in different regions of individual neurons. Thus a unique feature of this proposal is our use of a system that has the potential to demonstrate causal linkages between growth factor-mediated memory formation and the temporal and spatial features of the underlying synaptic mechanisms. PUBLIC HEALTH RELEVANCE: A major challenge in mental health is to achieve a basic understanding of the brain mechanisms that are engaged in normal memory formation, and how those mechanisms are impaired when memory is compromised by disease or injury, such as in Alzheimer's Disease, Post-Traumatic Stress Disorders, and in victims of accidents or strokes. Thus, the major focus of this project, understanding the molecular mechanisms whereby growth factors contribute to normal memory formation, can provide a means of developing effective therapies for a wide range of cognitive problems involving memory impairment.